Diagnosis of fertility status by folliculogenesis monitoring in the vagina

ABSTRACT

Methods and apparatus for interpreting vaginal measurement data by electronic means without the need for the user to take part in the data interpretation process. More specifically, an intelligent probe monitors folliculogenesis and correlates the ovarian function data to probe profile characteristics of the female reproductive cycle. A fertile window is defined with reference to the correlation between folliculogenesis and probe cyclic profiles. Data stored within the apparatus can be downloaded into an external display appliance or data analysis unit. Another aspect of the invention allows for continuous layout of the memory of preceding cycles in the inventory of the apparatus, retaining the most recent while erasing the most distant stored data. These methods assure a reliable fit for the diagnosis of fertility, treatment of infertility as far as timing of treatment procedures, management of subfertility and other gynecological disorders such as luteal phase deficiency or short luteal phase, and the management of premenstrual mood disorders, and of premenopausal and menopausal patients.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally concerns the field of intelligentmedical diagnostic devices. The present invention particularly concernsan apparatus and method for interpretation by electronic means of themeaning of vaginal measurement data without the need for the user totake part in the data interpretation process, and for optionaldownloading of the data stored within the apparatus into an externaldisplay appliance or data analysis unit. The apparatus and method areparticularly useful as an aid for the management of female patients withreduced fertility or infertility, and as a tool for natural orscientific family planning approach to birth control.

2. Description of the Related Prior Art

2.1 General Background and Problems with Competition Methods

The background of the invention of this application includes the morethan 3 million unintended pregnancies that occur annually in the U.S.,about half of which are attributable to contraceptive failure. The U.S.population of women that use some form of birth control comprisesapproximately 30 million to 40 million women. “There is no surer way toreduce the number of abortions in the U.S. and throughout the world thanby improving the effectiveness of contraception” [S. J. Segal, in E. E.Wallach and H. A. Zacur, editors: Reproductive Medicine and Surgery,Mosby, 1995]. Worldwide, there has been a tenfold increase in the use ofbirth control over the last 3 decades, the numbers exemplified by thealmost 400 million of contraceptive users in the developing world (in1994), and by the more than 50% of couples in the reproductive age groupthat practice birth control. In this context, the use of the so-callednatural family planning method is increasing for a number of reasons,including cost-effectiveness, health and religious considerations.Against the baseline statistics of a mere 10% to 20% chance ofconception from an unprotected intercourse for a normal healthy couplein any given month, the high incidence and increasing trend ofinfertility (approximately 20% in the U.S.) is the other side of thebackground of this invention. Infertility treatment is cruciallydependent on timing of procedures with respect to ovulation, and onindividualized procedures with careful monitoring.

On the basic level of the art, the issue or problem is how to detect oneor more reliable indicators of the fertility status which is infertileexcept for a few days at the so-called mid-cycle. The presentapplication addresses the next level which is how to utilize suchdiagnostically useful information in a user-friendly and reliable mannerso as to make it possible for the user to obtain directly the diagnosticdecision on whether fertile (conception can occur) or not fertile(conception cannot physically occur), without obligating the user tomake any decisions on how to interpret the measurement data. Theapparatus according to the inventions of this application performs thisdata interpretation automatically. The methods used for the electronicprobe data interpretation stem from a new understanding of thechronobiological meaning of the probe cyclic profile and of itsindividual features. This results in a method of assessing the periodicdevelopment of the egg in its protective microscopic sack (called thefollicle) as a function of at least two biological pacemakers or“clocks”.

One competitor that attempts to serve the purpose of electronicinterpretation of certain kinds of fertility data is the Personaelectronic colorimeter for urine analysis from Unipath Ltd. of Britain.It consists of detecting, in a woman's urine, both the luteinizinghormone (LH) surge that typically marks the ovulation day, as well as ametabolite of estrogen, i.e., another hormone which anticipates by aboutone day the luteinizing hormone surge. Since, unlike my probe, thePersona depends on biochemical reagents and since the supply of thereagents is limited, the user needs to estimate on which day of hermenstrual cycle she should start using the system. She does that basedon her history of menstrual cycles as though the length and the timingof the present menstrual cycle were the same as in her previous cycles.Because of variable lengths of successive cycles in most women, this isa weak feature in the design of the Unipath system. Even moresignificantly, this weakness is also involved in itsovulation-predicting method, which is based on data pooled from otherwomen and on the user's estrogen and LH data history, if available, bothstored in the Persona's memory.

The Persona Contraceptive System of Unipath Ltd. is an attempt at animprovement upon the commercially available luteinizing hormone (LH)kits that only aim to detect the LH surge in the woman's urine. Twobeneficial features have been introduced by Unipath Ltd.: 1. theaddition of an estrogen metabolite to the diagnostic measurement so asto anticipate the LH surge, and 2. the measurement is performedinstrumentally rather than as a subjective judgment of a color change bythe woman-user. However, ovulation as such is not detected by thePersona device. Ovulation is, in fact, known to fail to occur inapproximately 20% of the follicles that, triggered by the LH, undergothe cyclic event of follicle rupture. Ovulation also fails to occur withanother type of follicles, the so-called luteinized unrupturedfollicles. Yet, the LH surge can be seen in either case and is thereforea false indicator.

One other problem of the Persona is that the urinary concentration ofthe estrogen metabolite E3G peaks only within 24 hours prior to the LHsurge. This is not at all early enough to serve as a marker of thebeginning of the fertile phase. The Unipath literature states that “asustained rise in E3G can be used to identify the start of the fertilephase”, referring to a slow gradual increase that eventually becomes thepeak of E3G concentration. While the Unipath Persona PersonalContraceptive System has been introduced to the market in Britain, thestatistical testing for its reliability is still in progress. Theattempt by Unipath to use an ill-defined rise rather than the peak inthe cyclic profile of the estrogen metabolite is not a viable solution.Even if the ill-defined E3G rise in the urine were correlated with aclearly defined early stage of egg development towards ovulation, aserious flaw of the Unipath method is their reliance on pooled, ratherthan actual single-event, data in defining the start of the fertileperiod in a given cycle.

The gradual increase of the E3G concentration in the urine, proceedingat different rates in different cycles, can hardly be predictablyassociated with the beginning of the fertile period. Estrogen is knownto have both stimulatory and inhibitory effects on LH secretion and, tobe effective as a stimulant, must rise to its peak levels (>150 to 200pg/mi) and must remain elevated for at least 36 hours [J. Hotchkiss andE. Knobil in E. Y. Adashi, J. A. Rock and Z. Rosenwaks, editors:Reproductive Endocrinology, Surgery and Technology, Lippincott-RavenPublishers, 1996]. The E3G profile does not reflect the local interplaywith progesterone but only reflects clearance of one of at least 10metabolites of estrogen from peripheral blood circulation into the urineafter oxidative conversion in the liver. Whatever the rate of thisclearance process, there are local mechanisms due to which thequantification of ovarian steroids in peripheral blood or in urine isrendered “interesting but of little value in predicting the genitalend-organ effect” [C. J. Verco, in A. M. Siegler, editor: The FallopianTube. Basic Studies and Clinical Contributions, Futura PublishingCompany, 1986].

Ovarian vein-to-artery exchange of steroids, prostaglandins and otherbioactive substances is a local transfer mechanism. As such, it enableslocal regulation of ovarian, tubal and uterine functions, with genitalorgans therefore exposed at any given time to hormonal concentrationsthat are higher than the peripheral concentrations. This kind of acuteexposure is of particular relevance to the regulation of the physiologyof the genital organs. The local, as opposed to peripheral, bloodconcentrations of the steroid hormones are also believed to control theinnervation of the female genital tract. The cervix, like the isthmusregion of the fallopian tube, has a particularly dense innervation by,for example, the vasoactive intestinal polypeptide nerve [C. Owman etal., idem.]. These examples of local and acute regulatory mechanismsremain undetected by the prior art techniques that focus on peripheralvariables. Such peripheral or systemic techniques then resort to pooled,averaged, data as though synchronization of menstrual cycles weresomehow present.

The flawed assumption of similar timing of menstrual cyclic events fromone cycle to another has been a problem for the microprocessorcontrolled thermometers. Since the late sixties, the microprocessortechnology has been applied by a number of people to the well-triedbasal body temperature approach to family planning. These products arenot recognized as medically valid even if they may be acceptable to someof the older physicians. This is because of the fact that the so-calledbasal body temperature (BBT) is a systemic variable or a secondaryparameter that reflects, among other things, progesterone rise in bloodafter ovulation, usually one or two days later. Even though in somewomen in some cycles a dip in the temperature graph may be observed oneday before the post-ovulatory temperature rise, it is clear that the BBTmethod is of little value due to its lack of predictive capability anddue to its fundamental unreliability.

Another electronic fertility monitor that did attempt to anticipateovulation was the Cue fertility monitor from Zetek. It consisted of tworesistivity sensors: one oral (to detect a change in resistivity ofsaliva in the mouth some 5 or 6 days before ovulation), and one vaginal(to detect a change in resistivity of the mucus in the vagina, markingovulation). The Cue monitor measured the concentration of electrolytes,particularly common salt, in the saliva and in vaginal mucus. These areremote indicators of the physiological changes that are associated withthe fertility status of the cervical uterine tissues. The Cue monitorwas unreliable and it did not provide for a distinction between fertileversus not fertile days. It was also cumbersome to use, expensive, andnot at all feminine in any sense.

The inability to predict ovulation is inherent in U.S. Pat. No.5,209,238 (Sundhar, May 11, 1993) which purports to determineempirically the presence of a viable egg by detecting the simultaneouslyelevated readings of four vaginal measurements. The measured parametersare the basal body temperature (BBT), the concentration of luteinizinghormone (LH) postulated to be present on the vaginal wall surfaces, thealkalinity of cervical mucus (pH), and the viscosity of cervical mucusdetected as an increased pressure (p) on a thin diaphragm. The presenceof a viable egg is defined by Sundhar as all four parameters registeringabove respective threshold values which his patent leaves unspecified.

Sundhar states that the cervical fluid, which provides for the elevatedvalues of pH and p, appears at the mouth of the cervix only after therupture of the follicle. He states that the alkalinity and the densityof the mucous fluid are “the determining factors of ovulation”. He doesacknowledge the fact that the BBT becomes elevated only about 24-48hours after the rupture of the follicle to which he assigns its origin.He also appears to recognize that LH levels, on the other hand, peaksome 18 hours before the event which means that by the time ovulationoccurs, the LH is back to low levels. Regardless of whether he thereforeworks with parameters that do not, in fact, change at the time ofovulation and whether or not they change simultaneously to justify hisdefinition of the presence of a viable egg, the fact is that there is nocapability to anticipate ovulation by several days with his method andapparatus. Neither does his patent define the end of the fertile period(which in his terminology would be ‘viable egg no longer present’). TheSundhar patent does neither address nor satisfy the need for thedetermination of the window of fertility even if it does seek acorrelation between several parameters associated with the menstrualcycle. Sundhar does not include the day of cycle among his set ofparameters.

In contrast, Weilgain Precision Products Ltd. of Hong Kong have a U.S.Pat. No. 5,515,344 (Ng, May 7, 1996) teaching a menstrual cycle meterthat is a microprocessor-based calendar which basically provides for theday of cycle as the tracked parameter. The so-called menstrual cyclemeter calculates the fertile and infertile periods of the currentmenstrual cycle based on at least two previous cycle lengths and therespective first days of the cycles. The apparatus purports to indicatethe expected sex of a baby that is likely to be conceived on any givenday during the calculated fertile period. This purpose of the Ngmenstrual cycle meter may be controversial and the method isfundamentally flawed but the patent filed from Hong Kong may also betaken as evidence of public interest in fetal sex pre-selection in thecontext of small family planning.

In the U.S., this topic is often associated with Dr. L. Shettles, theauthor of the book “How to Choose the Sex of Your Baby” [Doubleday,1981]. According to “Dr. Shettles Method”, the critical variable forfetal sex preselection is the timing of intercourse with respect toovulation. Briefly, and without necessarily subscribing to it, I wouldnote that the method teaches that, to aim for a boy, intercourse shouldbe timed to occur on the day of ovulation or the day after; the moredifficult to pre-select female gender is to be aimed at by timingintercourse “several days before ovulation but preferably not closerthan two days before”. It will be clear from the description below thatthe intelligent probe of the present invention is eminently suited to bea timing tool in such a process.

The menstrual cycle meter of Ng is related to the Shettles Method. Theproblem with the Ng invention is that it relies on the old, failed,calendar or rhythm method of birth control. The method had failed interms of its high contraceptive failure rate resulting from itsassumption of similar timing of menstrual cyclic events from one cycleto another, one of the fundamental flaws discussed above in connectionwith the other prior art.

The erroneous assumption that women usually have 28-day cycles and thatthey ovulate on day 14 may cause problems even outside of the arena offetal sex-preselection. Problems can occur in standard monitoring ofpregnancy, if relying on the method or the date of the so calledpregnancy wheel. Indeed, miscalculations of the expected date ofdelivery, in the absence of diagnostic means such as ultrasound, haveeven led to the induced labor of many premature babies. It will beclear, from the description that follows, that the present invention hasuseful applicability also in pregnancy planning.

Weinmann's U.S. Pat. No. 5,240,010 (Weinmann, Aug. 31, 1993), filed fromIsrael, is another piece of evidence that electronic interpretation ofmultiple input data related to fertility does not necessarily lead to ameaningful acceptable solution of the problem posed by the need toanticipate fertility status changes, including the need to predictovulation. Merely processing a multitude of inadequate data inputs, inthe hope that synergistically they may achieve adequate fertilityprediction, does not do the job even if one of the inputs is somevaginal impedance parameter. Weinmann's other inputs are vaginaltemperature in lieu of the BBT for the end of the fertile period, and arhythm method calculation for the beginning of the fertile period.

2.2 The Need to Monitor Folliculogenesis

Monitoring of ovarian function is absent in competitors' prior art. Whatis missing in the cited prior art is a specific link between theemployed indicators and the events that occur well before ovulation,that is the link with specific early stages of ovarian function. Ovarianfunction in every menstrual cycle involves the formation and maturationof the dominant follicle in the ovary, followed by the follicle ruptureand the release of the egg (ovulation). Moreover, the prior art of thecompetitors does not work with the various biological pacemakers (suchas in particular the circamensual and the circhoral “clocks”) that areinherently involved in my present patent application. To be sure otherpacemakers exist in the reproductive system, including, significantly,one in the oviducts or fallopian tubes [S. Anand, in A. M. Siegler,editor: The Fallopian Tube, Futura Publishing Company, 1986], and theyare all likely to be involved in the dominant follicle's prerogative tosynchronize them (vide infra, this section).

Ovarian function and its significance for the invention cannot beunderstood without consideration of the fact that there are otherendocrine organs that communicate stimulatory or inhibitory signals tothe ovary and to which the ovary feeds back its signals. Since in thismanner there is a connection between the hypothalamus and the pituitarygland of the brain and the two ovaries, this connection is called thehypothalamic-pituitary-ovarian axis.

The mediators of communication among the organs are certain hormonesreleased into the blood circulation. As indicated in section 2.1, it issome of these mediator compounds that the competitors' prior arttargets, directly or even indirectly, as the handle on the timing of themenstrual cycle. Briefly, the peptide follicle-stimulating hormone(FSH), released by the pituitary, primarily functions to induceproliferation of the follicular granulosa cells in one of the twoovaries and to stimulate an aromatase enzyme (which is an electrontransfer enzyme) for estrogen synthesis. The other pituitary peptide,luteinizing hormone (LH), then stimulates the transformation ofestrogen-secreting stromal cells in the selected ovary intoprogesterone-secreting cells, and promotes ovulation. The predominantovarian hormones, that exert peripheral, central and intraovarianeffects, are the sex steroids estrogen or estradiol (E2) andprogesterone (P₄); there are also other steroids at play in the ovarianand hypothalamic-pituitary events. In addition, there are other peptidicreproductive hormones known as nonsteroidal ovarian factors (e.g.inhibin, oocyte maturation inhibitor, gonadotropin surge-inhibitingfactor and certain growth factors).

The properly orchestrated actions of all these substances are known tobe necessary for the functioning of the menstrual cycle. The endometriumand the cervix uteri are very sensitive detectors of the hormonalsignals and of their orchestration (i.e., of their relative timing withrespect to each other) [B. M. Sanborn et al., J. St. Biochem. 9:951,1978; G. I. Gorodeski et al., J. din. Endocrinol. Metab. 70:1624, 1990;G. Fried et al., Human Reprod. 5:870, 1990; G. I. Gordeski et al.,Fertil. Steril. 47:108, 1987]. The periodically recurring development ofovarian follicles, in preparation for the periodically recurringovulation, is called folliculogenesis. The process of folliculogenesisis the essence of ovarian function from the perspective ofovulation-prediction and it involves four basic conditions in which themany follicles, present in the two ovaries, can be found: resting,growing, atretic, or ready to ovulate [A. L. Goodman and G. D. Hodgen,in R. O. Greep, editor: Recent progress in hormone research, AcademicPress, 1983]. Most of the follicles remain resting but, at the beginningof every menstrual cycle, a group or cohort of follicles are recruitedto grow; only one of these will mature and will normally ovulate, withthe rest of the group succumbing to atresia (death).

It is well established that women and other primate females produce asingle fertilizable egg approximately every four weeks. The actualduration of this circamensual (or approximately one-month) period is nota constant; rather, it ranges from about three weeks to about five weekswherein lies the need for and the challenge of reliable monitoring ofthe menstrual cycle and of reliable anticipation of the brief fertilitywindow. The brevity of the fertile phase (about 5 days) is due to thelimited viability or life-time of the ovulated egg (i.e., the eggreleased from the successfully matured dominant follicle) coupled withthe pre-ovulation fertile days that are due to the life-time of thesperm which survive longer than the ovulated egg but only in thenow-hospitable environment of the cervical mucus and epithelium ataround the time of ovulation. Allowing for the longer longevity of thesperm is the most difficult challenge for scientific family planning.

Folliculogenesis is a continuous process with well-defined morphologicand endocrine dynamics or timing of events. The dynamics of this processhave been characterized biologically and separated into the intervals orstages of recruitment, selection, dominance and ovulation [G. D. Hodgen,Fertility and Sterility 38:28 1,1983]:

TIMING OF THE FOUR STAGES OF FOLLICULOGENESIS STAGES IN AN IDEALIZED,STEREOTYPICAL MENSTRUAL CYCLE RECRUITMENT SELECTION DOMINANCE OVULATIONApproximate cycle days 1 to 5 ± 1 6 ± 1 8 to 12 14 ± 1

The interval of recruitment begins at the end of the previous cycle,from the onset of menstrual bleeding to approximately day 5 7 of thecurrent cycle. During this interval, LH induces an “angiogenesis” factorfrom the theca cells, increasing the blood supply and estrogen synthesisby the recruited follicles.

The term “selection” indicates the reduction of the recruited group offollicles down to the species-characteristic ovulatory quota which inwomen and related primates is one. Selection is the culmination ofrecruitment on day 6±1. Typically only one of the two ovaries sponsorsrecruitment and selection of the single dominant follicle which isdestined for ovulation. (Spontaneous multiple ovulation is atypical,although not a rarity. It is expected that multiple ovulation should berecognizable with the probe of this invention.)

Dominance is the interval of follicular growth that precedes ovulationafter selection and is achieved typically between days 8 and 12 of thestereotypical menstrual cycle. It appears that the one follicle thatmost rapidly acquires aromatase activity and LH receptors probably isthe one that becomes dominant, overcoming an ovarian inhibitory activitythat suppresses the less-developed follicles of the recruited group, inthe midfollicular phase. The increasing quantities of estrogen aresecreted by the dominant follicle and play a critical role incoordinating the development of the different parts of the reproductivetract: estrogen priming is essential in the brain as well as in thecervical epithelium and mucus (where the probe detects its effect) andin the oviduct. The dominant follicle has a straightforward prerogative:it must synchronize the entire reproductive system for ovulation,fertilization and implantation. Failing that, conception will not bepossible (such as in the case of the luteal phase defect). This is theessence of the “pelvic clock” or “zeitgeber”, the ovarian circamensualpacemaker. However, the mechanism is made more complex by theparticipation of other pacemakers, including at least one in the brain,in the reproductive cycle (vide infra).

Once the dominant follicle has achieved the necessary size and adequatesystemic hormonal effects, final maturational changes within thefollicle stimulate ovulation. Endocrinologically, the most prominentmarker of impending ovulation is the LH surge which anticipatesovulation within 9 to 12 hours and which is under the control of theovarian pacemaker that dictates the timing of these events. At the timeof the LH surge, the granulosa cells surrounding the follicle becometransformed or “luteinized”. They become specialized toward synthesisand secretion of progesterone and this rapid increase in progesteronelevels is responsible for inducing and coordinating severalphysiological changes in the reproductive system; the ovulation markerdip or minimum of my prior art fertility probe detects one of them, dueto the sensitivity of the epithelium and mucus in the posterior fornixregion to the sex steroids.

2.3 The Kirsner Prior Art and the Present Invention

The present invention provides an improvement applicable to any othermonitor of the folliculogenesis process that has a similar capability toprovide a cyclic profile with this high information content in onevariable. Based on the repeatability of the characteristic profilefeatures from cycle to cycle, the data makes it possible to interpretthe probe cyclic profile so as to recognize the various phases offolliculogenesis and, in so doing, to distinguish the brief fertilitywindow from infertility and thus anticipate ovulation in a rationalmanner.

FIG. 10 depicts the features of a menstrual cyclic profile that wasyielded by a woman answering the idealized, stereotypical or baselinecharacteristics. The length of the cycle and its apparent dynamics (ortiming of the various intervals or stages involved in folliculogenesis)are chosen to correspond to the stereotypical case of 28 day-longmenstrual cycle. The first minimum, FM, occurs in this cycle on day 6and reflects the selection stage that is the culmination of recruitment.We are justified to view the depicted data on day 6 as FM even m theabsence in this particular profile of the prior data points that werenot obtained on account of hygienic considerations during the previousdays of menstrual bleeding; many other cyclic profiles have consistentlyshown this first minimum, as illustrated in FIGS. 11 and 12.

FIG. 10 further depicts the wide and high first peak FP that describesthe interval of dominance. This is then followed by the window offertility WF which is defined by boundaries BF (begin fertility) and EF(end fertility) with three labeled features flanked by the boundarypoints, all within the window WF. These five days define the fertileperiod during which conception is possible due to the life-times of boththe egg and the sperm with the proviso stated below in the discussion ofthe data interpretation program in relation to the need for large-scalestatistical data confirming this definition of WF.

We know from empirical evidence that the third minimum, labeled OM,marks the day of ovulation because in separate experiments it coincidedwith the day of the LH surge detected in the subject's urine by standardlaboratory procedure, radio-immunoassay. (OM also always preceded therise in BBT when monitored for comparison.) It will be clear to thoseskilled in the art that ultrasonic evidence of follicle collapse is amore reliable proof of ovulation, if backed by other data eliminatingthe possibility of follicle collapse without egg release; however,ensuing pregnancy is the only definitive proof of ovulation in absoluteterms. Such proof will be obtained in a planned clinical trial,discussed below. The temporal relationship (one day) between theovulation marker OM and the second peak SP is consistent with a steroidsignal from the selected ovary signaling its readiness to release theegg from the dominant follicle.

The most important feature to point out about FIG. 10 is that, while thetwo horizontal thresholds FT and OT are constants dependent on thecalibration of the probe electronics, the boundary days of the fertilitywindow WF (BF and EF, here days 12 and 16) are variables that changefrom cycle to cycle. This is documented in Table 1 (Window of fertilityboundary days for six menstrual cycles). Table 1 shows cycles with cyclelengths ranging from 24 to 30 days, with the beginning of fertility BFranging from day 9 to day 13, and end of fertility EF ranging from day13 to day 17. The Table demonstrates how seriously wrong the assumptionof the same timing of events in different cycles would be if theassumption were used for the data interpretation method, as has been thecase in the prior art by certain competitors. The Table shows that twocycles of a given cycle length (here 26 days) can have two differentbeginnings of the fertile window (here day 9 and day 13, respectively).The Table also shows that a given beginning of the fertile window (hereday 13) can occur in cycles of different lengths (here cycle lengthsfrom 24 to 30 days).

I now introduce a new discovery that is most important for theconstruction of the data-interpretation program described and claimedbelow. Due to the mandatory synchronization of the various pacemakersinvolved in the natural cycling process of the reproductive system,there appears in the probe cyclic profile a phenomenon that I describemore fully below under the name of “synchronization arrest”. Inconnection with it, I have now discovered that the beginning offertility, BF, is predicted by the amplitude of the probe signal on theday of the first minimum, FM; this is also depicted in FIG. 10.

TABLE 1 WINDOW OF FERTILITY BOUNDARY DAYS FOR SIX MENSTRUAL CYCLES BF EFOM Beginning End of Ovulation Length of Cycle of Fertile Fertile Lengthof Marker Luteal Number Window Window the Cycle Day Phase A. BASELINECYCLES PM1 12 16 28 15 13 PM2 13 17 30 16 14 PM3  9 13 26 12 14 Baseline9-13 13-17 26-30 12-16 13-14 Range B. NON-BASELINE CYCLES LK4* 13 18 2617  9 LK5 13 17 24 16  8 LK6 13 17 28 16 12 Non-baseline 13 17-18 24-2815-16  8-12 Range Overall 9-13 13-18 24-30 12-16  8-14 Range *Cycle LK4is a short cycle, as are cycles PM3 and LK5 (<28 days). However, unlikecycle PM3, cycles LK4 and LK5 are abnormal cycles with short lutealphases (<11 days). Both have abnormally long follicular phases, beingshort cycles, unlike the baseline cycle PM3 which is short simplybecause of its short follicular phase (with the normal luteal phase of14 days). Cycle LK4 is unusual in that there are three, ratherthan justone, decreasingreadings after A the second peak. Cycle LK4, which wasrecorded by a woman with a history of amenorrhea and of ovarian cystsbefore her two pregnancies, is considered to be a case of asynchronybetween follicle maturation and the pituitary signal to ovulation [A. J.Zeleznik, in E. Y. Adashi and P. K. C Leung, editors: The Ovary, Raven,1993, pp.41-45; G. F. Erickson in J. Schoemaker andR. Schats, editors:Ovarian Endocrinopathies, Parthenon, 1994, pp. 103-115; E. L. Nestour etat, J. Chin. Endocrinol. Metab. 77: 439, 1993], involving the circhoralclock of the hypothalamic GnRH pulse generator on which the circamensualovarian clock is “obligatorily dependent’ IJ. Hotchkiss and Knobil in E.Y. Adashi, J. A. Rock and Z. Rosenwaks, editors: ReproductiveEndocrinology,Surgeiy, and Technology, Lippincott-Raven Publishers,1996].

The multitude of repeatable measurable features of the probe cyclicpattern makes it possible to determine the boundaries of the fertilewindow for every individual cycle rather than having to rely on someassumption of unchanged timing of these events from cycle to cycle inthe manner of the methods of prior art discussed above. The Kirsnermethod of electrometric monitoring of the tissues and secretions in theposterior fornix region for the end-organ effects of the endogeneousbioactive substances is a significant improvement upon the use of thehormone concentrations by the prior art competitors such as Unipath Ltd.Reliance on the hormone concentrations to define the fertile period isan inherently unreliable approach because the hormones are merely theinput signals into the physiological mechanism of fertility statusrather than indicators of the fertility status per se.

Monitoring of the end-organ effects may produce two kinds of deviationsfrom the idealized, stereotypical menstrual cycle. These deviations fromstereotype are variously considered to be consequences of the industrialand post-industrial age lifestyle, diet and environmental estrogens or,more generally, pollution. Chemically-speaking, free radicals andabnormal cross-linking of macromolecules in the tissues are ofteninvolved. These are electron transfer reactions whose effects aredetectable by the Kirsner probe but not by the other prior arttechniques including the Unipath Persona. Those techniques cannottherefore detect the deviations from “norm”, or stereotype, which is onereason why the concept of the stereotypical menstrual cycle continues tobe perpetuated in the literature. The deviations of the first kind arethe merely quantitative variations of the idealized menstrual cycle,leading to near-stereotypical cyclic profiles such as those included inFIGS. 11 and 12. The other kind of deviation is more serious, causingqualitative changes diverging from the stereotype, leading to aberrantcyclic profiles associated with reduced fertility and femaleinfertility; this includes, for example, the case of the quitefrequently occurring luteal phase defect (FIG. 22). Even some of thenear-stereotypical profiles may turn out to reflect more than biologicalvariables, and may be found to represent a syndrome (e.g., the shortluteal phase cycles LK4 and LK5, particularly cycle LK4). Adjustments tothe programming of the intelligent probe may result from the forthcomingclinical trials. Any such adjustments will be within the scope of thisinvention.

SUMMARY OF INVENTION

The inventive apparatus and method include:

-   -   discovery that probe cycle profile is tied into        folliculogenesis, the process of preparation for ovulation    -   how the profile correlates with the individual events or        intervals of folliculogenesis (ovarian function)    -   how this correlation enables fitting data points into the        profile which leads to a method that translates the intuitive        thinking process of an expert into the logics of a formalized        data-interpretation method    -   that reliability of the fit, i.e. of diagnosis, can be        quantified    -   method of this quantification and of its display by the        instrument    -   factoring into the confidence level descriptor the statistics of        conception probability for the day, established in a clinical        trial designed around the single-attempt requirement that        guarantees homogeneity of the data.    -   method of fitting data either into extended or into partial        context of prior data inventory in the present cycle    -   definition of fertile window, i.e., defined with reference to        probe profile features including the instant recognition of BF        via its prediction by earlier profile features (FM, g, etc.)    -   method of using clinical trial data to define the numerical        ranges for each of a number of inter-related characteristic        features of the cyclic profile as qualifiers for compliance        queries in the cross-correlation process of data interpretation        (this contrasts with competitors' reliance on a fixed average        value of a single feature such as the Unipath Persona's use of        the E3G threshold)    -   miniaturized single piece format of probe    -   user friendly combination of hardware and software features        (hardware features in the form of simple buttons and        alpha-numeric display in natural language) e.g. allows days set        to be entered late; does not interrogate user beyond minimal        requirements    -   I-button to register intercourse makes it possible to        electronically record intercourse for pregnancy-planning        purposes, including 1) calculation of expected date of delivery        and 2) fetal sex preselection probability assessment    -   method of data management for optional downloading into an        external display appliance    -   method of data management for optional data offloading for        memory clearance, in relation to limited capacity of the memory    -   method of enabling continuous use of the intelligent probe        despite the memory size limit    -   continuous layout (e.g., rectangular or circular) of the memory        makes it possible to avoid full memory preventing continued        functioning, by erasing the oldest stored data and preserving,        by this design, the most recent stored cyclic profiles    -   day set button for day 1 or +1 or −1 is oval shaped, press and        rocker combination (allows also to set day belatedly or to        change the setting)    -   download initiation control is turn-screw on back, independent        of daily use (to conserve energy and to simplify use)    -   Web TV download capability and capability to download on        ordinary TV with a decoder-interface unit    -   capability to recognize an abnormal cyclic pattern as either a        non-classical profile of a fertile cycle or as an aberrant        profile of an infertile cycle (present method applies to        classical profiles and, through the “complies?” query in the        second decision routine, to non-classical profiles by extension)    -   complementary or alternative method of data interpretation,        called the method of normalized or, generally, transformed data

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a partial perspective view of a preferred embodiment of theintelligent fertility monitor of the invention, showing the arrangementof user-interface features appearing, in this embodiment of theapparatus, at the front or top side and at the bottom.

FIG. 2 is full front view thereof depicting the user-interface and otherfeatures on the front or top side of the apparatus.

FIG. 3 is the right side view thereof depicting the controls on the backviewed from the side.

FIG. 4 is a rear view thereof depicting the controls on the back as seenfrom the rear.

FIG. 5 is a block diagram of the electronics of the intelligent probedepicted in FIGS. 1 to 4.

FIG. 6 is a flow diagram of the program associated with the actuation ofthe intercourse-register I-button 316 in FIG. 3.

FIG. 7 is a flow diagram of the program associated with the actuation ofthe download control 314 in FIG. 3 that initiates the downloading intoan external display appliance for viewing.

FIG. 8 is a flow diagram of the routine, within the downloading programof FIG. 7, that either offloads the complete contents of the intelligentprobe memory for the purpose of memory clearance or, alternatively,erases some of the downloaded cycles from the display on the externaldisplay appliance.

FIG. 9 is a flow diagram of the simple data manipulation routine withinthe downloading program of FIG. 7, that performs shifting of the probedata along the time (day of cycle) axis.

FIG. 10 depicts the probe cyclic profile that corresponds to astereotypical menstrual cycle of 28 days duration and is labeled withthe features of the profile so as to establish the terminology for thedata-interpretation program of the present application.

FIG. 11 shows three baseline cyclic profiles discussed in theapplication.

FIG. 12 shows three non-baseline cyclic profiles discussed in theapplication.

FIG. 13 is a flow diagram of the routine that performs the dailyinitiation of the intelligent probe measurement by examining or settingthe day of cycle (relative time clock).

FIG. 14 is a flow diagram of a bookkeeping subroutine, within theinitiation routine of FIG. 13, that checks the number of previouslystored cycles against a preset limit and prompts the user to offloaddata once the limit has been reached and, if the user is not in aposition to clear the memory, the subroutine makes room for the newcycle by erasing the oldest of the previously stored cycles.

FIG. 15 is a flow diagram of the routine that performs the measurement.

FIGS. 16A and 16B provide flow diagrams of the routine performing thesecond decision which is whether today's data is post-ovulatoryinfertile (after end of fertility EF) or not.

FIG. 17 is the routine of a decision as to whether the data of todayfits before the first peak (also referred to as the long-term predictivepeak) and means therefore infertile diagnosis, or whether it fits at orafter the first peak.

FIG. 18 is the routine of the decision as to whether the data fits wellbefore the second peak, meaning infertile, or whether it fits at thesecond peak SP (also referred to as the short-term predictive peak) orone day before, which is the beginning of fertility BF, or one dayafter, which is the end of fertility EF.

FIG. 19 depicts the probe cyclic profile of an aberrant cycle due to anapparent luteal phase defect (LPD).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to electronic interpretation of data,monitored in relation to the day of cycle, on the physiological state ofthe cervix uteri and cervical mucus by means of the probe of my priorart patent application, and to automatically providing a display of thecurrent fertility status. This is based on the measurement with theprobe depicted in FIGS. 1 to 5. The electronics of the probe contain amicrochip, preferably an application-specific integrated circuit with amicroprocessor, that performs the measurement as well as the datainterpretation and data management according to the methods and programsof the present invention.

FIGS. 1 to 4 are perspective, front, side, and rear views of theintelligent probe. FIGS. 1 to 4 resemble a fertility probe of my priorart, in particular they resemble the mammalian fertility probe of mydesign patent application filed under docket number 9064/102 to which Iam now adding new features that provide for the intelligentcharacteristics of the apparatus of this invention. The probe comprisesseveral cylindrical sections, preferably three as shown. The firstsection is a rigid or semirigid cylindrical body 11 approximately 10centimeters long and 1 centimeter in diameter. The first section 11 hasa rounded distal or insertion end insertable into the vagina, with theinsertion end extending into the region of the posterior fornix withelectrode 211 of FIG. 2 contacting the cervix. Two electrodes orelements 211 and 312 in FIG. 3 are embedded into probe body 11. Theelectrodes 211 and 312 can be of any shape and size within reason. Theattachment of the electrodes to the body can be accomplished by anymethod known for attaching an electrode to a substrate, including, butnot limited to gluing, bonding and embedding. The cylindrical body 11 ofthe first section may be modified in any of the ways anticipated by mypatent application “Method and apparatus for monitoring fertility statusin the mammalian vagina” filed under docket number 9064/101.

The second section 12 may be of a larger diameter but smaller than thethird section, as shown, but this mid-size diameter is a cosmetic ratherthan a functional feature. The second section contains three functionalelements, one on the top or front side and two on the back. An infra redor other data transfer interface port 14 appears as a small opening onthe front side defined as the side that carries the display-cum-controlswell 15 and the electrode 211. On the back side of this section are, asseen in FIGS. 3 and 4, two wells 313 and 315 with two buttons 314 and316 that are provided to control the less frequently used functions. Thescrew-like button 314 initiates, by being turned 90 degrees, datadownloading once the port 14 is lined up with the corresponding port ona data receiving device. This function is independent of and separatefrom the daily-use program, in order to conserve energy and, equallysignificant, to keep the operation user-friendly (undemanding). Thewell-recessed small button 316 is used to register intercourse and saveits timing (day of cycle) in the memory of the intelligent probe. Eitheror both controls 314 and 316 may be behind a little door (or twoseparate doors) protecting them further from accidental actuation. Otherpossible embodiments of the I-register input control include a slidingswitch that slides from one groove into another and back, or two buttonsthat may be concentric and must be pressed together.

The port may be located in the third section instead of in the indicatedposition, interchanging the location with the “confirm” button 19, inanother embodiment of the apparatus of this invention. It could also belocated closer to the well 15, either on the second section 12 or on thethird section 13.

The third section 13 carries most of the microelectronics and is thehandle of the hand-held probe device. The oblong narrow well 15 carriesthe ON button 16 at the proximal end, followed by the LCD (or LED orother) display 17. This is then followed by the special control 18 whichis a rocker switch that enables either positive (+) or negative (−)response to a displayed question, or adding 1 to (+) or subtracting 1from (−) a displayed numerical value. The control switch 18 also makesit possible to perform its key role, which is the initialization of theday of cycle counter (or relative time clock), by being pressed straightdown in its flat middle portion, where the numeral 1 is seen embossed orotherwise imprinted on its surface. Other possible embodiments of thecontrol element 18 include three separate buttons or other switchesperforming the same roles. They could be located outside of the well 15such as on the opposite, back, side of the third section 13.

At the proximal or non-insertion end of the intelligent probe is the“confirm” button 19 located in a crater-like well 10 the purpose ofwhich is to prevent accidental actuation of the control 19. In anotherembodiment of the intelligent probe, the “confirm” button 19 and thewell 110 are not present because the role of the “confirm” button isperformed by the plus (+) segment of the controls 18 (or by a separatebutton as noted above in discussing other possible embodiments of thecontrol button 18. The space in which the “confirm” button 19 is nowshown in FIG. 1 may be utilized for an external power supply connectionuseful for data downloading (and/or offloading) under the control of theintelligent probe. This preserves battery life for the daily use of theintelligent probe.

FIG. 5 is a block diagram of the electronic configuration of the probeof the invention which involves a microchip, preferably anapplication-specific integrated circuit. The electrodes 501 and 502 areactuated by means of the electrode interface conditioning electronics503 by a waveform digitally generated by the microprocessor 507. Thewaveform is applied after conversion into an analog signal in the A toD/D to A converter 505 which then also converts the electrode responseto digital data for processing by the microprocessor 507. Unlike in theprevious generation of the fertility probe, data processing now includesthe data-interpretation treatment which is the subject of thisapplication. The processed data is displayed on LCD (or LED or other)display and stored in memory 506 for use as context for datainterpretation on following days of the present menstrual cycle; thestored data can also be optionally downloaded later (for display andanalysis) via the input/output interface 508 into an external device509.

The external device is typically a personal computer which may bededicated to this purpose of analyzing patient data in a physician'soffice. It may also be a decoder-interface unit custom-made for thepurpose of receiving the data from the probe for display on an ordinarytelevision set or on the new generation of computer-TV hybrids (such asthe Web-TV, for example). A Web-TV may be equipped with an infrared portand may thus be able to receive the data directly, without thedecoder-interface device. For such a case in particular, the intelligentprobe includes an embedded program for elementary manipulation of theTV-downloaded multiple cyclic profiles, for the user's convenience. Inthis way, the intelligent probe may provide access to the new generationof the so-called natural family planning to almost any woman in anyhousehold, regardless of whether they do or don't own a home computer.This is useful since TV set ownership is generally more widely spreadthan personal or home computer ownership.

FIG. 6 is a flow diagram of the program associated with the use of theintercourse-register I-button 316. This routine is independent of thedata-interpretation program and of the daily-measurement procedure; itis initiated by pressing the I-button 316 and terminated automaticallyby switching power off once the entry into the I-register is completed.The routine allows for a belated retrospective entry and for a possiblyuncertain timing of such a retrospective entry. In the event thewoman-user forgets to register the intercourse on the day, and thenlater wants to do this retrospectively but is not certain of the timeelapsed, the routine downgrades reliability of the I-register.

Under the preferred normal circumstances, the user activates theI-registering routine on the day of the intercourse. The function of theI-button 316 commences with START I-REGISTER ROUTINE block 600 andproceeds to look up in today's memory location the day of cycle XX(and/or date) in block 601. This is then queried in block 602. Inresponse, the LCD 17 displays the entry “I on day XX?” as a questionwith a flashing question-mark, prompting the woman to confirm this ininquiry block 603 (XX represents here today's day of cycle, e.g., 09 or15, as the case may be) by pressing the “confirm” button 19. Upon thisconfirmation, the question-mark is extinguished as an acknowledgment ofthe confirmation and the entry is made in the I-register as in block604, and the power is turned off in Block 605. Repeated entries on thesame day simply write over without further changing the I-registerstatus, i.e., intercourse on a given day is registered whether itoccurred and was entered once or more than once.

If the woman is making the registration on a following day, today's dayof cycle XX is not confirmed in inquiry 602 by pressing the minus signon button 18, and consequently the inquiry KNOW HOW MANY DAYS AGO? ismade in block 606. In response she either steps the I-register downusing button 18 by one day or by whatever number of days she remembersas the elapsed time with confidence, or she registers her uncertaintyfirst by setting the flag in block 607, before setting the I-registerback in block 608 by the guessed number of days using again button 18.The uncertainty will eventually be displayed on the downloaded cyclicpattern graph as “I?” instead of the definitive “I”. Either thedefinitive “I” or the uncertain “I?” will appear on the time (day ofcycle) axis of the graph and also by or in place of the respective datapoints in the line graph displayed on the external device 509. Therealtime, calendar date, will also be displayed. The calendar dateinformation is useful for the purpose of calculating the estimated dateof delivery, in case of conception resulting from the intercourse. Theday of cycle information may be used for the purpose of fetal sexpreselection.

A similar design approach is adopted for the control of the optionaldata downloading into a display appliance (external device 509), whetherit be a personal computer or a Web TV or the proprietarydecoder-interface unit for interfacing with an ordinary TV set. Theguiding principle is again to achieve user-friendly simplicity andpower-supply energy conservation. FIG. 7 is a flow diagram of theprogram associated with the use of the download control 314. Theprogram, which commences with START DOWNLOADING block 700, first enablesto decide, through the inquiry of block 701, whether to download datavia blocks 702 (HAVE SOFTWARE?) and 703 (TRANSFER CONTROL TO PC) into apersonal computer which then can take control over the downloadingprocess; or whether the downloading will be into another displayappliance that is devoid of the required software. In the latter case, asimple data manipulation is made possible by the intelligent probe usingthe few already described elements of the user interface, containedwithin the third section 13 of the apparatus.

FIG. 7 describes the process of downloading, i.e., data-copying, underthe control of the intelligent probe. Any amount of data may bedownloaded for display on the external device 509, whether only thepresent cycle or all stored cycles or anything between these twoextremes. However, only the total of the raw data can be offloaded so asto make the probe's memory all available again for new data. The user isnot allowed to edit the data for offloading while she can manipulate thedata for viewing on the external display appliance 509, the simpledisplay manipulation sub-routine being described in FIG. 9 (shiftingdata along the day of cycle axis). Care is taken to allow offloading,for external archive storage, only of the complete set of raw data,unaffected by the manipulation available in the display sub-routine(particularly the option to erase or display only some of the storedcyclic profiles).

Once the decision has been made in block 701 to download under thecontrol of the intelligent probe, the inquiry is made in block 704whether only present cycle data is to be downloaded. If so, copying ofdata proceeds as per block 705 (using the confirm button 19). With thatcycle displayed on the display appliance, additional cyclic profiles maybe added to the display via blocks 706 (ADD ANOTHER?), 707 (KEY INNUMBER=C−i) where C is the present cycle number and i is an integer forcounting cycles backward, and finally block 708 (COPY DATA). Negativeresponse to the inquiry in block 704 allows to download all storedcycles (via block 709) or almost all after selective deletion in block710. Either option goes to the sub-routine of FIG. 8. Negative responseto the inquiry in block 706, namely no more stored cycles to bedisplayed, proceeds to exit in block 712 via the inquiry 711 whichallows for a change of mind on the part of the user who may, uponviewing the present cycle data, decide to view all stored cycles ratherthan adding some of them piecemeal as already described.

The remainder of the logical elements in FIG. 7 describe the functionsperformed upon return from the two sub-routines shown in FIGS. 8 and 9.The inquiry in block 713 allows the user to remove some cycles from thedisplay on the external appliance upon return from the “offload ormerely view” sub-routine of FIG. 8. This is achieved by means of blocks714 (identifying the cycles to remove, 715 erasing) and 716 (deciding towhether to exit or whether to remove some more data for a simplifiedviewing display prior to eventual exit via block 712). The inquiry ofblock 717 handles the return from the “simple display manipulation”sub-routine of FIG. 9. The feature to note in FIG. 7 is that the womancan first examine the data selectively, before returning to offload thetotal memory contents in its raw state.

FIG. 8 is a flow chart of the sub-routine that offloads the entirememory contents of raw data. After block 800 has copied the data, theinquiry is made in block 801 whether to offload or not. The userresponds via the plus or minus control 18, possibly in combination withthe confirm button 19. If affirmative, the entire memory is transferredin block 802 into the external appliance capable of receiving the data(e.g., a personal computer), the sub-routine is exited and theintelligent probe is powered off (in block 803). If the user does notwish (or cannot) offload, the program goes into the sub-routine of FIG.9 via the connector C. Also included in FIG. 8 is a return from thesub-routine of FIG. 9 via the connector D. This allows the user tochange her mind, in block 804, and offload the previously viewed andmanipulated data but only after the data set has been returned to itsraw state: to that end, the displayed data is erased in block 805, thenthe entire memory is copied again in block 800 and offloaded via blocks801 and 802 as already described.

FIG. 9 performs the rudimentary data manipulation that is ofsignificance to any woman interested enough in the history of hermenstrual cycle data to wish to review it on a display screen. The “rawstate” of the consecutive cycles is a sequence showing the severalmonths worth of menstrual cycles one after another so that the last dayof cycle i is also the first day of cycle i+1 as per the well knownconvention. The sub-routine first enables a decision in block 900 (bymeans of the plus or minus functions of the control 18, possibly incombination with the confirm button 19) whether to display the data onthe same time scale, i.e., in the manner of FIG. 11 or FIG. 12. If so,all the data are shifted accordingly. After a time delay, the nextinquiry is in block 902, namely, does the user want to synchronize thedisplayed cyclic profiles on the day of the ovulation marker (SYNCHRO ONt=OM?). This inquiry would also be arrived at had the previous type ofdisplay not been desired by the user. The shift is performed by block903 and, after a time delay, the sub-routine connects with theoffloading sub-routine via connector D, as already discussed in FIG. 8above.

A very important feature of the design is the option, open to thewoman-user, to continue using the probe without offloading (i.e. withoutclearing up) a full memory. This is achieved by retaining the mostrecent preceding cycles in the inventory and erasing the most distant,the oldest stored data; she therefore always has the most recent history(whether it be six or twelve cycles or whatever the limit capacity builtinto the apparatus) available for examination. This is made possible bythe continuous layout of the memory discussed below in connection withthe bookkeeping routine for stored prior cycles.

The main control button 16 initiates, by switching on the power, thedaily measurement and its diagnostic interpretation. Thedata-interpretation program interprets today's probe measurement data:it develops the diagnostic meaning of the data in terms of fertilitystatus (either fertile or infertile). It does that by cross-correlatingthe amplitude of the probe signal with at least one other runningvariable, day of cycle, as measured by the instrument's clock which mustbe set to day 1 on first day of menstruation. (Other measurementvariables may be introduced to potentially increase the quality ofinterpretation at the cost of increased complexity of the program and ofincreased production cost of the probe.)

“Cross-correlation” means to answer the question: What probe datainterpretation is consistent with the other running variable, namely theday of cycle? The method used in this application is based on fittingdata points into a curve that has a multitude of reproducible features.Other methods, known to those skilled in the art (such as artificialintelligence methods) are to be considered as falling within the scopeof this invention.

The data-interpretation program is based on the reproducibility of thefeatures of the probe cyclic pattern (or “profiles). The characteristicfeatures of the profiles were described in section 2.3 with reference toFIG. 10 and further experimental evidence is illustrated by threebaseline and three non-baseline patterns in FIGS. 11 and 12. The threebaseline cyclic profiles in FIG. 11 were obtained with three probemonitors PM1, PM2, and PM3 by three clinical trial volunteers whosatisfied the criteria for baseline characteristics. They were perfectlyhealthy young women below the age of 35 (here 26 to 30 years of age) whoused no medication and no contraception. They had no prior pregnanciesand they were non-smokers. The term “baseline” refers to the fact thatthese women were characterized by minimal, if any, potentialcomplications of physiological or biochemical nature that could causedeviations from a norm or baseline; they were as close to the idealized,stereotypical menstruating female as can be.

The baseline cycles in FIG. 11 exhibit at least two importantcharacteristic features that were not known at the time of filing myU.S. '247 patent and the subsequent patent applications. One, the dataof the first minimum, FM, predicts the amplitude of the probe signal onthe day of the beginning of the fertile window, BF, which is the end ofthe interval of dominance (refer to FIG. 10). And two, the end of thedominance interval is followed by a slowdown in the descent of the probesignal from the first peak, FP (into the second minimum, SM) whichanticipates the ascent forming the second peak. I refer to this slowdownas a “synchronization arrest”. I consider both these characteristics aconsequence of the ovarian mechanism that regulates the antral fluidsteroid milieu, i.e., an indicator of the intrafollicular hormonalprofile of the dominant follicle [E. Y. Adashi, J. A. Rock, and Z.Rosenwaks, editors: Reproductive Endocrinology, Surgery, and Technology,Lippincott-Raven Publishers, 19961.

Those skilled in the art of reproductive physiology or endocrinologywill appreciate the significance of these phenomena, tied to thepreviously mentioned (section 2.2) prerogative of the dominant follicleto synchronize the entire reproductive system in order to makeconception possible. The “synchronization arrest” is significant alsowith respect to the short luteal phase phenomenon as illustrated by twoof the non-baseline cycles in FIG. 12 (cycles LK4 and LK5). I believethat the mechanism involved in some maimer the brain, probably thecirchoral clock (the hypothalamic GnRH pulse generator) on which thecircamensual ovarian clock is obligatorily dependent; or this could be acase of failed gonadotropic (LH) support by the brain for the corpusluteum's pre-programmed luteolytic self-destruct mechanism. It issignificant that the details of the luteolytic control mechanism inprimates are yet to be worked out [ibid. idem.]. The complexity of themeasurements of the differences between intrafollicular and circulatinglevels of hormones adds to the significance of the two probe profilecharacteristic which reflect what is going on in the ovary.

The three non-baseline cyclic profiles in FIG. 12 are three consecutivemenstrual cycle probe records by a subject who did not satisfy thebaseline criteria. Mrs. LK was not “chemically clean” because she was acigarette smoker; she also routinely ingested various nutritionalsupplements that may have affected her reproductive biochemistry andphysiology. She was over the age limit of 35 and had some history ofamenorrhea, and of ovarian cysts diagnosed years earlier by palpation.She was also a mother, unlike the baseline subjects. In the years beforeher pregnancies, her cycles were consistently rather long, at 34 or 35days (as opposed to her cycle lengths here of 24, 26, and 28 days). Thenon-baseline cyclic profiles in FIG. 12 nevertheless exhibit the samefeatures as those in FIG. 11 that were obtained under more controlledlaboratory conditions.

The non-baseline profiles do present certain quantitative deviationsfrom baseline: namely, in two cases (cycles LK5 and LK6) their dynamicrange is significantly lower compared to the baseline cycles in FIG. 11,and their post-ovulation (luteal) phase is not of the normal, inherent,length of 14 days (12 to 16). In such cycles with short luteal phases(<11 days), observed more often in older women, there is a lack ofsynchrony between the ovarian and the menstrual events due to aluteal-phase mismatch between the ovarian steroids and the pituitarypeptides (S. K. Smith et al., J. Reprod. Fert. 75:363, 19851. Mrs. LK'shistory of amenorrhea and ovarian cysts is pertinent to the case ofshort luteal phase. However, so is stress and its effect on the GnRHhormone generator in the hypothalamus of the brain, that affects theoutput of the pituitary peptides. For example, it is known in a generalway that norepinephrine and possibly epinephrine in the hypothalamusincrease the GnRH pulse frequency. Conversely, the endogeneous opioidpeptides, the enkephalins and beta-endorphin, reduce the frequency ofthe GnRH pulses. These interactions are particularly important at thetime of the mid-cycle LH surge, affecting its timing and intensity [W.F. Ganong, Review of Medical Physiology, 17th edition, Appleton & Lange,1995, Chapter 23]. The slow rate of descent of the data from SP to OM isa useful diagnostic variable that differentiates cycle LK4 from cycleLK5. It is indicative of an extended period of time required in cycleLK4 for the two “clocks” (the circhoral and the circamensual) to becomesynchronized as a precondition of ovulation. Further, these “real life”(non-laboratory) records also contain gaps in data and possible effectsof improper sensor positioning, in addition to the deviations from“ideality” (or stereotype). They therefore present a “real life” testfor the data-interpretation program.

The program does not analyze the data beyond the one day after theovulation marker day because that is the postovulatory infertile phaseof any menstrual cycle by definition. It is noticeable though that boththe baseline and non-baseline profiles exhibit repeatable postovulatoryfeatures that are consistent with known biological facts and are likelyassociated with the pulsatile release of progesterone from the corpusluteum (the postovulatory entity formed from the former dominantfollicle). These postovulatory features may be of use in a futureextension of the program; they may also be of use in a future extensionof the applicability of the apparatus and method beyond that discussedhere.

The structure of the data-interpretation program, as shown in Table 2,consists of numerous layers of routines within two blocks, i.e., BlockI=Preparation for Interpretation and Block II=Interpretation of Today'sProbe Data.

TABLE 2 BASIC ELEMENTS OF THE PROBE DATA INTERPRETATION PROGRAM Block I.Preparation For Interpretation 1) Cycle day/initiation of measurement2) Today's probe data 3) Inventory of data in present cycle Block II.Interpretation Of Today's Probe Data First decision: Single-shot (1A) orcontextual diagnosis (1B) If 1A, go to single-shot routine If 1B,continue Second decision: Postovulatory (2A) or not (2B) If 2A,infertile - unless ovulation + 1 (fertile) If 2B, continue Thirddecision: Before long-term predictive peak (3A) or after long-termpredictive peak (3B) If 3A, infertile If 3B, continue Fourth decision:Before short-term predictive peak (4A) or at short-term predictive peakplus 1 day before (4B) If 4A, infertile If 4B, fertile continue Fifthdecision: Assess reliability of interpretation as one of the following:1. highly reliable diagnosis fixed readout 2. moderately highreliability of diagnosis “fast spelling” readout 3. moderately lowreliability of diagnosis “slowly spelled” readout This decision is basedon: a) number of data points used as context for today's datainterpretation b) conception statistics for today's day of cyclec) reproducibility of data upon optional repetition (if any)d) amplitude of today's probe data with respect to thresholdse) uncertainty, if any, about the day of cycle (first day setting)

The routines of the first block, Preparation, establish the informationrequired for data interpretation: today's cycle day, today's measurementdata, and the “inventory” of prior data, if any, from previousmeasurements in the present cycle as may be stored in the probe'smemory.

The routines of the second block perform the actual interpretation: theprocess consists of making five decisions on whether today's probemeasurement is consistent with infertile or with fertile interpretationand how reliable that diagnostic assessment is. The program looks forthe much more frequent infertile diagnosis before looking to confirmfertile diagnosis, in the following systematic manner. First, it decideswhether today is the first, so far the only, measurement in the presentcycle which demands a “single-shot” diagnosis, or whether a contextualinterpretation will be made possible by previously measured and storeddata providing a context for today's data point and thus increasing thereliability of the interpretation. If contextual interpretation is madepossible by previously stored data in memory, the second decision iswhether the today's data point fits the characteristics of postovulatorydata. If postovulatory, the interpretation is infertile unless the datafit the characteristics of ovulation marker+1 day (which requires theinterpretation of fertile).

If the outcome of the second decision is not postovulatory datacharacteristics, the third decision is whether the data fits thecharacteristics of data before or after the first peak FP (the long-termpredictive peak); if before, then the interpretation is infertile. Ifthe outcome of the third decision is that the data point fits thecharacteristics of data after the first peak, the fourth decision ismade on whether the data fits far enough before the second peak SP (alsoknown as the short-term predictive peak) which means infertile orwhether it fits at the second peak which means fertile. For the datapoint of today to fit at the second peak means that it corresponds toone of the characteristic features of the second peak as discussed below(Table 4): Either to SM or to SP or to OM, the three data points thatdefine the peak.

In either case, the fifth decision follows to assess the reliability ofeither of the diagnostic conclusions (fertile or infertile). Thereliability descriptor is one of three degrees: 1. High reliability, 2.Moderately high reliability, 3. Moderately low reliability. Thereliability assessment is a function of several factors: a) the numberof data points from this cycle's inventory that have been used fortoday's data contextual interpretation, b) the conception statistics fortoday's day of cycle referenced to the characteristic feature of thecyclic profile including the ovulation marker and the long-termpredictive peak, c) the reproducibility of the measurement data if theuser opts to repeat the measurement within the allowed two hours, d) theamplitude of today's probe data with respect to the fertility thresholdand the ovulation threshold which in certain instances increases thereliability more than in others depending on day of cycle (e.g., dataabove 220 on day 9±1 increases the reliability of infertileinterpretation), and e) the uncertainty, if registered, about thecorrectness of the day of cycle which may have arisen upon theinitialization of the day of cycle counter (relative time clock) if theuser forgot to do this on day 1 of the cycle (i.e., on the day of herfirst menstrual bleeding).

Each time the display of the intelligent probe is to indicate either“fertile” or “infertile” according to the flow diagrams in the figuresbelow, the diagnostic interpretation is stored along with the raw dataand a connection is made with the routine of the fifth decision(reliability assessment). A relatively high reliability of thediagnostic data interpretation is then indicated by a steady appearanceof the fertility diagnosis on the LCD display, versus a relatively lowreliability of the diagnostic data interpretation which is indicated byslow, letter by letter, emergence of the word “fertile” (or “infertile”as the case may be) on the display, in such a manner that the completeword never appears but rather the “spelling” is repeated at least twice.This focuses the user's mind on the fact that the diagnostic statementis relatively unreliable, although it is always more reliable thanmerely guessing the fertility status based on the day of cycle alone (asin the discredited so-called calendar or rhythm method of birthcontrol). The only truly indeterminate situations, no better than theday-of-cycle based guess, arise from the discouraged possible use of theintelligent probe in the inadequate-context diagnostic mode such as inthe single-shot diagnosis discussed below. The LCD display thenindicates “unsure” or similar indication of indeterminate diagnosticinterpretation. In recommended use, a moderately high reliability of thediagnostic interpretation of data is indicated by fast emergence, i.e.,rapid spelling of the diagnostic outcome on the display, revealing thecomplete word (“fertile” or “infertile”) for a brief moment beforerepeating the fast “spelling” procedure at least four times.

In summary, there is an unambiguous, easily intuitively understooddistinction made between the different confidence levels of thediagnostic data-interpretation statements. Either diagnostic statementis available on the display for a limited period of time; if this turnsout to be insufficient, the user can easily bring the result up again bysimply pressing the “on” button 16 again.

With reference to the reliability decision about the confidence level ofthe diagnostic interpretation, the quality requirements of theconception statistics, particularly in terms of homogeneity of the data,must be emphasized. In so far as the reliability descriptor of thefertility status diagnosis is one innovation of this application, and inso far as the conception statistics are factored into the descriptor,this point is of utmost importance. The clinical trial, that willgenerate the data on the conception statistics with reference to thelong-term predictive peak, is yet to be performed. The basic requirementof the trial must be the single-attempt requirement: The womenparticipating in the trial will be required to make a single attempt atconception in the cycles they contribute to the trial. At least fourcycles each will be required. The women will be divided into severalgroups that make single attempts at conception on different days ofcycle after their long-term predictive peaks. In this manner, theprobabilities of conception will be established statistically forindividual cycle days, allowing for the tonic growth phase of the antralfollicle. It is planned to finalize the design of the reliabilityassessment routine at that time.

The numerical values of the measurement data in Tables 3 to 5, just asthose in the graph of FIGS. 10 to 12, pertain to the particularcalibration of the particular preferred embodiment of the method andapparatus of the invention discussed in this patent application. Thequalitative aspects of the probe profile features listed in Tables 3 to5 similarly pertain to the particular embodiment of the apparatus andmethod utilized here for the purpose of teaching the invention. It is tobe understood that the characteristic features of the cyclic profiledepend on, and change with, the particular biological species to whichthe probe may be applied as well as with the waveform selected and, moregenerally, the characteristic features depend on and change with themode of electrode excitation and the mode of monitoring. The data inFIGS. 10 to 12 and in Tables 3 to 5 are provided by way of examples,without prejudice to the scope of the invention.

TABLE 3 CHARACTERISTIC FEATURES OF THE PROBE CYCLIC PATTERNPOSTOVULATORY FEATURES High day number (t > 17) Day number may be 12 < t< 17 with data d < 150 Low peak values (d < 200) Later peaks are higherthan earlier peaks OVULATION MARKER Data amplitude approx. 95 (85 < d <105) Follows on two predictive peaks Occurs only on days 12-17PREOVULATORY FEATURES Low day number Occur never after ovulation Highpeak values (d > 200) First minimum on day 7 ± 1 First minimum on day 8for otherwise on day 6 Second minimum on day 12 ± 2 First peak startsfrom day 7 ± 1 Second peak starts from day 12 ± 2 Two peaks only shortcycles, Lone-term predictive peak features Starts from day 7 ± 1 Doesnot occur after ovulation marker or after short-term predictive peak Ifdata goes x days up then it goes x ± 2 days down High readings (d > 200)Apex on day 9 or day 10 Short-term predictive peak features Starts fromday 12 ± 2 Occurs after long-term peak Does not occur after ovulationNarrow width 1-3 days, mostly one day Apexondayll-15 Amplitude within arange

Table 2 summarizes the structure and basic elements of thedata-interpretation program. In the tabulated systematic manner, mostdiagnostic interpretations are made with a high degree of confidence,due to the high information content of the probe cyclic pattern. Thehigh information content is summarized in Table 3 (Characteristicfeatures of the probe cyclic pattern). The wealth of characteristicfeatures allows certain diagnostic interpretations to be made morereadily, and/or with a higher reliability of the diagnosis, than others.For example, ovulation marker is readily and reliably determined if allthe conditions are satisfied as follows: today's reading is between 85and 100 uA and two peaks have occurred beforehand with the features ofthe predictive peaks as listed in Tables 3, 4, and 5. In the case of theovulation marker, the diagnosis is also quite reliable even if made inthe absence of extended context information in the probe memory.

Table 4 lists the numerical details of the characteristic features ofthe second peak of the probe cyclic profile, also called the short-termpredictive peak.

TABLE 4 CHARACTERISTIC FEATURES OF THE SECOND PEAK, SP (THE OVARIAN PEAKA.K.A. THE SHORT- TERM PREDICTIVE PEAK) SHOWN IN DATA-POINT COORDINATESt, d Cycle Number BF SM SP OM g_(up) g_(down) A. BASELINE CYCLES PM1 12,158 13, 150 14, 211 1592 61 119 PM2 13, 183 14, 150 15, 215  16, 100 65115 PM3  9, 235 10, 142 11, 218  12, 88 76 130 B'aseline 9-13, 158-18310-14, 11-15, 12-16, 88-100 61-76 115-130 range 142-150 211-218 B.NON-BASELINE CYCLES LK4 13, 135 13, 135 14, 158  17, 96 23  50 LK5 13,129 14, 128 15, 162  16, 95 34  67 LK6 13, 178 14, 164 15, 220  16, 10256 118 Non- 13, 129-178 13-14, 14, 15, 158-220 15-16, 23-56 50-118baseline 128-164 95-108 range Overall 9-13, 129-183* 10-14, 11-15,12-16, 88-108 23-76 50-130 range 128-164 158-220 Key: t = time [day ofcycle], d = probe data [microamperes], BF = beginning of fertilitywindow, SM = second minimum, SP = second peak, OM = ovulation marker,g_(up) = d_(SP) = d_(SP−1,) g_(down) = d_(SP) − d_(SP+1). *Except forPM3 which is a short cycle with a short follicular phase and its BFtherefore anomalously coincides with the apex of the first peak (whichotherwise precedes BF by several days in cycles with longer follicularphases)

Table 4 is the list of the characteristics of the second peak thatoccurs within the window of fertility:

-   a) the start of the peak, i.e., the second minimum SM is within the    range of cycle day 10 to 14 and its amplitude ranges from 128 to 164    uA;-   b) the peak day coordinate of SP is within the range of cycle day    11-15 and the range of its amplitude coordinate is 158-220 uA;-   c) the ovulation marker OM occurs within the day of cycle range    12-16 and its amplitude range is 88-108 uA;-   d) the timing of the second peak of the non-baseline cycles does not    deviate from the baseline range of the respective cycle days;-   e) amplitude-wise, the deviation from baseline of the non-baseline    range of probe measurement data is, as consistent with expectable    estrogenic differences between baseline and non-baseline subjects,    most pronounced at the peak's apex (downward) and least pronounced    at the ovulation marker minimum which is reproducible within the    narrow range noted under c) above;-   f) the gradient of the ascending (gup) and of the descending (gdown)    branches of the second peak SP are high in comparison to the top    sections of the first peak. Where the non-baseline data are within    the range of the first peak, they anticipate the short luteal phases    of those cycles;-   g) the beginning of fertility (BF) data are within the range of    cycle day 9 to 13 and their amplitude ranges from 129 to 183    microamperes. This range excludes cycle PM3 which is a short cycle    with a short follicular phase that causes a too high BF reading that    lies, in fact, at the apex of the first peak. The anomalous first    peak of cycle PM3 is a consequence of the short follicular phase    which has clearly recognizable high gradients comparable with the    high gradients of the second (fertile) peak;-   h) the lowest second peak of the six (158 uA in cycle LK4) is    associated with an unusually slow descent into the ovulation marker    minimum.

TABLE 5 CHARACTERISTIC FEATURES OF THE FIRST PEAK, FP (THE DOMINANCEPEAK, A.K.A. THE LONG-TERM PREDICTIVE PEAK) SHOWN IN DATA-POINTCOORDINATES t, d Cycle Cycle Number FM FP BF g_(up) g_(down) Length A.BASELINE CYCLES PM1 6, 158 10, 265 12, 158 25 45 28 PM2 6, 182  9, 27513, 183 15 20 30 PM3 8, 128  9, 235  9, 235 107  93 26 Baseline 6-8,128-182 9-10, 235-275 9-13, 158-183* 15-25* 20-45* 26-30 Range B.NON-BASELINE CYCLES LK4 8, 137 13, 135 26 LK5 8, 138 13, 129 12 25 24LK6 13, 178 28 Non- 8, 137-138 12-13, 12 25 24-28 baseline 129-197 rangeOverall 6-8, 128-182 9-10, 235-275 9-13, 129-183* 12-25* 20-45* 24-30range Key: t = time [day of cycle], d = probe data [microamperes], FM =first minimum, FP = first peak, BF = beginning of fertility, g_(up) =d_(FP) = d_(FP−1), g_(down) = d_(FP) − d_(FP+1). *Except for PM3 whichis a short cycle with a short follicular phase and its FP day istherefore not infertile

Table 5 lists the characteristics of the first peak FP, also referred toas the long-term predictive peak or the dominance peak:

-   a) The start of the peak, i.e., the first minimum FM, is within the    range of cycle day 6 to 8 and its amplitude ranges from 128 to 164    uA.-   b) Cycles shorter than 28 days have the FM on day 8 and therefore    record the prior descent to the minimum whereas longer cycles have    the FM on day 6 (meaning that the descent was completed during the    menstrual bleeding period of days 1 through 5).-   c) Comparing the amplitude range of the first minimum with the    amplitude range of the BF data listed here as well as in Table 4    (from FIGS. 11 and 12) reveals that the BF range of amplitudes    (beginning of fertility) is approximated by the range of the first    minimum. The amplitude of the FM therefore anticipates the amplitude    of the BF data. Provided that we exclude the short luteal phase    cycles (that are distinguished by the steep gradients of the first    peak), this finding can be used to identify the beginning of    fertility BF on the day it occurs (in extended context-data    interpretation), rather than identifying BF retrospectively from SM    and SP data.-   d) The peak day of FP is within the very narrow range of cycle days    9 or 10 and its amplitude is 200 uA and above.-   e) The gradients g_(up) and g_(down) are low: excluding the short    cycle PM3 because of its short follicular phase (associated with its    anomalously narrow, low and sharp first peak), the gradients are    distinctly lower than those of the second peak.

FIG. 13 is a flow diagram for the daily initiation of the diagnosticmeasurement, the main purpose of which is to examine and, ifappropriate, to set the relative time clock that counts the days ofcycle starting on the first day of menstrual bleeding. The routine isuser-friendly in several ways. It allows the user to set day 1retrospectively, if she forgets to do so on her first day of menstrualbleeding, although this causes a downgrade in the reliability assessmentof any subsequent diagnostic interpretation of the data. The downgradingof the confidence level is more serious if the user forgets to set day 1on day 1 and then only guesses how long ago day 1 was. However, sincethe shape of the cyclic pattern is more significant than the day ofcycle alone, even this downgrade is not too serious in extended-contextdiagnosis. The user is asked to confirm the correctness of the daycounter (relative time clock) setting in the first eight days of cycle,i.e., during the first three or so post-bleeding days, far from havingto go through this interrogation every day.

The initiation of the daily measurement and its interpretation commenceswith START block 1300 and proceeds to inquire in block 1301 whether therelative time t (day of cycle) is greater than 18. This relative-timeboundary condition of the fertile window is used here-by way of examplewithin the frame of reference of the cyclic data in FIGS. 11 and 12. Theparticular numerical value of t=18 is used, rather than the generalt=EF, with the proviso that its final numerical value, to be imbeddedinto the intelligent probe according to this invention, will depend onthe outcome of the large-scale clinical trial invoked above inconnection with the assessment of data-interpretation reliability in thediscussion of Table 2. Therefore, the value to be adopted as the resultof the clinical trial may be larger than 18. Clearly, should the“statistical extension” of this limit be too high, the program would beextended to rely on analysis of the shape of the postovulatory part ofthe cyclic profile rather than on a particular numerical value asadopted here.

If the day of cycle counter shows greater than 18, then block 1302 makesthe interpretation of INFERTILE TILL NEXT CYCLE and displays thisindication on the LCD display 17. Block 1303 then inquires whether todayis the first day of the next cycle which the user judges by the presenceor absence of menstrual blood flow. The confirm button 19 or, in anotherpreferred embodiment, the positive side of control 18 is used to confirmthe first day if blood is found to be present and to confirm this inresponse to block 1304 (SURE?). If not sure, the inquiry 1303 isrepeated until a definitive answer is provided. If the response to 1303is negative (by means of the negative side of control 18), then block1306 inquires again whether bleeding and receives negative responsecausing exit and power off in block 1307. If bleeding is present eventhough today is not the first day, then block 1308 inquires into howmany days ago. If known with certainty, then block 1309 allows the daynumber to be keyed in, using any or all three functions of control 18(1, +, −, in any combination but logically starting with 1 and adding toit if more than one day). If not known for sure, block 1310 downgradesthe reliability of the answer before proceeding to enter the less thancertain number of days since bleeding started. Block 1309 also caps thecount of days in the completed cycle (now “previous cycle”) so as toeliminate any overrun due to the fact that the first day was notregistered when bleeding actually started. These decisions are queriedfor correctness in block 1311 which allows for rectification of anymistakes by going again through the loop of the inquiry of block 1308,either with certainty (simply correcting a possible miskeyed answer inblock 1309) or further downgrading reliability in block 1310.Confirmatory response to the SURE CORRECT? inquiry of block 1311 leadsto another BLEEDING? inquiry of block 1312. This differentiates betweenthe first five or so days when readings are obviated by menstrualbleeding (block 1313: WAIT TILL STOP BLEEDING) and the commencement ofmeasurement in the new cycle for which the program goes into the routineof FIG. 14 via connector 1.

Returning to the first inquiry of this routine in block 1301, if theanswer were negative, the next inquiry in block 1314 is as to whetherrelative time (cycle day register) has been set. If not, the justdescribed loop beginning with query 1303 (TODAY FIRST DAY?) is entered.This allows for belated start of monitoring in the present cycle. Thelast element in this routine is the inquiry in block 1315 (t<9?) which,for practical reasons based on experience, gives the user another chanceto make a correction of the day of cycle setting every day during thefirst three or 50 days after the cessation of menstrual blood flow.Since women know that these early days are infertile, some may be slackon the routine procedure and so this loop gives them a chance to rectifyany mistakes due to belated start of the day of cycle counter.

Since this relative-time clock routine handles the initiation of newcycles, it must also handle the bookkeeping of previous cycles inrelation to the memory space available for data storage. The flowdiagram of this bookkeeping function is in FIG. 14 and it uses a counterof stored cycles, C, which is stepped up upon completion of the presentcycle (i.e., the start of the next cycle, indicated by the start ofmenstrual bleeding). The design of the intelligent probe allows for alimited number, CLIM, of menstrual cycles to be stored, prompting theuser to offload the stored data once the limit has been reached. Onepreferred limit is twelve menstrual cycles and this is based on theclinical definition of infertility which involves absence of conceptionafter twelve months of unprotected intercourse; another preferred limitis six months which tends to prompt an earlier consultation with aphysician if reduced fertility is a problem.

The bookkeeping aspect of this routine is based on continuous structureof the memory, such as a circular structure with a delineated point offirst entry. The day of cycle, measurement and ancillary (e.g., cyclenumber intercourse registered, diagnosis and reliability) data for everyday are stored in a continuous manner, including gaps should the userskip the daily measurement. Upon starting a new cycle by setting day 1in the start-up routine depicted in FIG. 13 which connects with thisbookkeeping routine via connector 1, the cycle counter C is stepped upin block 1401 and compared with the limit, CLIM, allowed for the numberof stored cycles (block 1402). When the limit is reached, the user isprompted to offload the data (user instructions will recommend aphysician's office visit in case of difficulty to conceive). The promptto initiate the download is in block 1404 which is predicated by apositive response to the inquiry of block 1403 as to whether the womanhas a capability to offload.

Even if she is not in a position to offload and thus renew the memoryavailability, the user is likely to have enough memory space left tocontinue, via connector 2, since allowance is made for long cycles(e.g., forty days long). Availability of memory space is queried inblock 1405. In the absence of the offloading clearance, the memory willbe filled up eventually and when the “not enough memory left” conditionis detected in block 1405, the software erases, in block 1406, theoldest stored cycle data. This is where the continuance (e.g., circularor more likely rectangular layout) of the memory comes into play, so asto facilitate the erasure of the oldest data before the more recentlystored data may be treated in the same manner, should the user continueusing the probe without offloading. This design secures the availabilityof the most recent inventory or history of the woman's menstrual cycleseven in the event of having exceeded the memory limit (whether it be sixor twelve or any other number of previously stored cyclic profiles).

The fact that the intelligent probe can never refuse to perform thedaily measurements on account of an over-filled memory is an importantand essential aspect of its user-friendly design. It is to behighlighted, however, that for the many near-stereotypical cycles ofaround 28 days in cycle length, there is an approximately 30% sparememory space available because of the allowance for approximately 30%longer cycles in the setting of the limit CLIM. The greater the numberof cycles allowed to be stored (GuM), the greater the favorable impactof this design feature. All the stored data, including the “extra”cycles are accessible for offloading and downloading. The remainingelement in this routine is block 1407 which is a bookkeeping inquiryinto whether the data is overflowing the memory limits (handled asdiscussed above) or whether it is still below the CLIM in which case theprogram goes to the next routine.

FIG. 15 is a flow diagram of the routine that performs the actualmeasurement once the time coordinate has been ascertained. This routineis again user-friendly in that it allows the user to repeat her dailymeasurement should she feel compelled to do so within two hours of firstuse. (The time of daily measurements is a personal choice and the userinstructions advocate to adhere to the selected time of day, give ortake an hour.) Any new measurement data for today is written over thedata stored in today's memory location within the allowed two hours. Acomparison with the previous data of today, if any, is made because thereproducibility of the measurement data, in case of more than onemeasurement, becomes a factor for the reliability (confidence level) ofdiagnosis assessment in the fifth decision of the data-interpretationprogram (not shown). The routine charted in FIG. 15 also performs thetask of optionally repeating the display of today's fertility diagnosis,whether the user wishes to merely check the status or whether she wishesto repeat the measurement within the allowed two hours of the firstmeasurement of the day.

The routine starts with an inquiry in block 1501 as to whether today'smemory location is still empty in which case block 1502 starts theancillary hours counter just before block 1503 takes the actualmeasurement (instructing the microprocessor 507 to actuate theelectrodes 501 and 502, and to record the response; the instructions arenot shown). If the memory location is not found empty by block 1501,block 1504 instructs the microprocessor to display the data from today'smemory location and then the diagnostic interpretation of that data.After a brief period of time, sufficient for user's assessment of thedisplayed information, block 1505 tests the hours counter that had beenstarted in block 1502 and, if the time elapsed is within the two hoursallowance of the first measurement of today, block 1509 allows the userto repeat the measurement by means of block 1503. If the elapsed time isbeyond the two hour limit introduced at block 1505 or if the user doesnot wish to repeat the measurement in block 1509, the previous data anddiagnosis of today's fertility status are displayed again in block 1506after which, following again a suitable delay for user's contemplation,the routine is exited and the intelligent probe is powered off in block1507.

Returning to the preferred extended-context mode of data interpretation,FIG. 16A is a flow diagram of the routine that makes the decision,whether the data taken today is postovulatory infertile (i.e., after theEF boundary of the window of fertility), or not. The routine starts theexamination of this cycle's inventory of data on the earliest dayavailable in C memory (preferably day 6 or earlier), having initializedthe counters of peaks and minima by means of which it looks for thepostovulatory condition. The postovulatory condition is defined byhaving found in the inventory of the present cycle, prior to today'sdata, two peaks and three minima, all complying with the characteristicsof the two predictive peaks and the associated minima, plus the day ofcycle coordinate must correspond to two days after the third minimumwhich is the ovulation marker. The characteristics that this routinerefers to are those listed in Tables 4 and 5 (numerical ranges ofrespective coordinates). As pointed out in the discussion of Tables 4and 5 above, these characteristics pertain to the particular calibrationand, more generally, to the particular mode of electrode excitation andthe mode of monitoring in the particular embodiment of the apparatus andmethod of the invention.

The decision routine is written out in two parts, FIGS. 16A and 16B,because of its length and complexity. The chief reason for thecomplexity is the possibility of gaps in the flow of data, should theuser skip some daily measurement(s) and the possible occurrence of noisein the data. Both these complications are present in the examples ofnon-baseline cyclic profiles in FIG. 12. The second part of the routinein FIG. 16B re-defines as noise any lack of compliance of a detectedpeak or minimum with the characteristic features of the follicular phaseof the profile. This is then recognized in the subsequent routines ofthe third and fourth decisions as a factor for downgrading thereliability of the diagnostic interpretation of the data.

The first element of the routine, block 1901, clears out the peaks andminima counters and the second, block 1902, instructs the microprocessorto seek or look up next day data (it has just found the earliest data ofthis cycle in the preceding routine). The third block, 1903, inquires asto whether the search has reached today's date yet and if so, the peaksand minima counters are interrogated, in succession, in blocks 1905 and1908, respectively, as is the condition of today's day of cycle t (T=OM+2?) in block 1911. The subsequent steps are identical for all the threeinquiries of blocks 1905, 1908 and 1911 if the answers are negative:blocks 1906, 1909 and 1912, respectively, inquire whether no gaps werefound; if so, the program goes into the routine of the third decision(FIG. 17) whereas if the answer is negative since gap(s) found, theprogram goes into the fourth decision routine (FIG. 18).

FIG. 17 is a flow diagram of the routine that makes the decision if theoutcome of the previous, second decision in FIG. 16A was “notpostovulatory”. The decision is whether the data fits before the firstpeak which means infertile diagnosis, or whether the data fits at orafter the first peak. The condition of before the first peak is P=0 andM=1 (registers P and M count the peaks and minima, respectively) and ittranslates as infertile. If the condition is not satisfied (i.e., morethan one minimum and at least one peak have been found), the fourthdecision is to be made next.

FIG. 18 is a flow diagram of the routine of the decision which must bemade if the outcome of the previous decision was “not before the firstpeak”. The decision is whether the data fits well before the second peakor at any of the five points of the fertility window: the three pointsthat define the second peak or one day before the “foot” of the peakwhich means one day before the second minimum, meaning the beginning offertility BF, or one day after the ovulation marker (i.e., the third)minimum, meaning the end of fertility EF. The conditions queried in thedecision routine of FIG. 18 have been dealt with earlier and thefertility window has also been defined. End of fertility EF−OM +1 (endof fertility is defined as one day after ovulation marker OM). Ovulationmarker OM=d<OT (ovulation threshold) & P=2 (ovulation marker is definedby measurement data below the ovulation threshold and the peak counterregistering two peaks). Second peak SP is defined by P>1 & M=2 &155<d<225 & 10<t<16. Second minimum SM is defined by M=1&P=1 & 125<d<165& 9<t<15. Beginning of fertility BF is defined by M=1 & P=0 & 125<d<240& 8<t<14 or BF is defined by M=1 & P=1 & d.sub.BF=d.sub.FM+−10. This iswhere the characteristic features of the first and second peaks comeinto play and the program looks them up just like the human expert does:namely in a list such as those in Tables 4 and 5.

The second part of the routine of the decision described in FIG. 16Babove is also important for another reason in addition to that discussedabove. The compliance queries therein are also the points where aberrantfeatures of a qualitatively deviant cyclic profile are discerned andseparated from the merely quantitative deviations such as thoseexemplified by the data in FIG. 12. This separation is achieved byproviding to the program another set of characteristic features thatbelong to another type of cyclic profile.

An example of an aberrant cyclic profile is shown in FIG. 19 depicting acase of an aberrant luteal phase defect (LPD) which occurred m aperfectly healthy, 25 year old woman. This defect, a frequent cause offailure to conceive, is characterized by a complete absence of the firstand second peaks. This means that the telltale signs of the reproductivesystem preparing for ovulation, by going through the stages offolliculogenesis as described above, are completely absent in thisaberrant cyclic profile. As such, this qualitative deviation from theclassical or baseline profile is readily characterized for recognitionby the intelligent probe's microprocessor. The diagnostic indicationthroughout the cycle is “infertile-LPD”. Both the woman-user and herphysician have the benefit of early recognition (by day 10) of thedefect, a significant benefit in the context of infertility management.

1. A method for diagnosing fertility status in a female mammalcomprising the following steps: a. monitoring folliculogenesis of saidfemale mammal by means of a fertility probe which generates ovarianfunction data; b. correlating said ovarian function data to a probecyclic pattern generated by said fertility probe in response to saidmonitoring, wherein said probe cyclic pattern includes a first peak anda second peak which occur in said probe cyclic pattern prior to anovulation marker, wherein said first peak includes an ascending partwhich begins at a first minimum and a descending part which ends at asecond minimum, and wherein said apex of said first peak has thegreatest amplitude in said probe cyclic pattern; c. defining within saidprobe cyclic pattern a portion of said descending part of said firstpeak between an amplitude about equal to said first minimum of saidfirst peak and an amplitude about equal to said second minimum of saidfirst peak; and d. predicting an occurrence of a fertile window basedupon the portion which occurs prior to the ovulation marker.
 2. Themethod of claim 1, further comprises the step of correlating saidovarian function data with said part of said probe cyclic pattern whichincludes said second peak having an ascending part which begins at saidsecond minimum and a descending part which ends at an ovulation markercorrelating with the point of least amplitude in said probe cyclicpattern.
 3. The method of claim 2, further comprising the step ofcorrelating said ovarian function data with said part of said probecyclic pattern which includes post-ovulation peaks having an ascendingpart which begins at said ovulation marker, and wherein said fertilitywindow ends upon correlation of said ovarian function data with saidpost-ovulation peaks for a period of about 24 hours.
 4. The method ofclaim 3, wherein said step of monitoring folliculogenesis of said femalemammal by means of a fertility probe which generates ovarian functiondata, further comprises the step of locating at least one of twoelectrodes to engage the cervical epithelium in the posterior fornixregion of the vagina.